Compositions and methods for the treatment of musculoskeletal related diseases and disorders using metal ion-citrate analog complexes

Abstract

The invention is directed to a composition and associated method for the treatment of musculoskeletal related disorders and diseases. In particular, the present invention provides a class of citrate compounds that can be used to for the treatment of diseases/disorders characterized by the degeneration of musculoskeletal tissues including menisci, bone, articular cartilage, and soft tissues. Examples of suitable citrate and citrate analog compounds include citrates having the following base formula (I): where X may be one of the following: wherein Y, Y′, and Y″ are independently a citrate moiety, O, O—Y, OH, NH, NH—Y, R and R—Y, with R being an alkyl, alkyene, ester, aryl, or phenyl group having from 1 to 6 carbon atoms.

That which is claimed: 
     
       1. A method of treating a musculoskeletal disease or disorder comprising the step of administering to a subject in need thereof an effective amount of a composition comprising a citrate compound or a pharmaceutically acceptable salt thereof that is complexed with a metal ion, wherein the musculoskeletal disease or disorder is posttraumatic osteoarthritis, and wherein the citrate compound has the following formula: 
       
         
           
           
               
               
           
         
       
       where X is one of the following: 
       
         
           
           
               
               
           
         
       
       wherein Y is a citrate moiety, O, OH, NH, or R; Y′and Y″ are independently a citrate moiety, O, O—Y, OH, NH, NH—Y, R or R—Y, with R being an alkyl, alkene, ester, or aryl group having from 1 to 6 carbon atoms; and Z is a carboxyl group, H, or R. 
     
     
       2. The method of  claim 1 , wherein the ratio of metal ion to citrate compound is from about 1:6 to 2:1. 
     
     
       3. The method of  claim 1 , wherein the composition is administered at a dosage from about 2 mg to 200 mg/kg body weight. 
     
     
       4. The method of  claim 1 , wherein the composition is administered orally. 
     
     
       5. The method of  claim 1 , further comprising administering chondroitin sulfate, pentosan polysulfate, or a combination thereof. 
     
     
       6. The method of  claim 1 , wherein the disorder or disease is further characterized as osteoporosis or invertebral disc degeneration. 
     
     
       7. The method of  claim 1 , wherein the disorder or disease is associated with meniscal degeneration, meniscal tears, meniscus transplantation, and combinations thereof. 
     
     
       8. The method of  claim 1 , wherein the metal ion is selected from the group consisting of magnesium (Mg), calcium (Ca), strontium (Sr), iron (Fe), zinc (Zn) and combinations thereof. 
     
     
       9. The method of  claim 1 , wherein the citrate comprises phosphocitrate and the metal ion is selected from the group consisting of sodium, magnesium, iron, and calcium. 
     
     
       10. The method of  claim 1 , wherein X is 
       
         
           
           
               
               
           
         
       
       and Y″ is O; Y′ and Y are OH. 
     
     
       11. A method for treating a musculoskeletal disease or disorder comprising the step of administering to a subject in need thereof an effective amount of a composition comprising a citrate compound or a pharmaceutically acceptable salt thereof that is complexed with a metal ion, wherein the citrate compound comprises a compound having the following base formula (I): 
       
         
           
           
               
               
           
         
       
       where X is one of the following: 
       
         
           
           
               
               
           
         
       
       wherein Y is a citrate moiety, O, OH, NH, or R; Y′and Y″ are independently a citrate moiety, O, O-Y, OH, NH, NH-Y, R or R-Y, with R being an alkyl, alkene, ester, or aryl group having from  1  to  6  carbon atoms, and wherein the musculoskeletal disease or disorder is posttraumatic osteoarthritis. 
     
     
       12. The method of  claim 11 , wherein the metal ion is selected from the group consisting of magnesium (Mg), manganese (Mn), calcium (Ca), strontium (Sr), iron (Fe), zinc (Zn), aluminum (Al) and combinations thereof, and the ratio of metal ion to citrate compound is from about 1:6 to 2:1.